1. Field of the Invention
The invention relates to 2-pyrimidyl alkanesulfonates, methods for their preparation, and methods for their use in preparing 1-(cyanoalkyl)-4-(2-pyrimidyl)piperazines (which are in turn useful materials for producing compounds having pharmacological utility as tranquilizing and anti-emetic agents).
2. Description Relative to the Prior Art
It is known that 8-[w-[4-(2-pyrimidyl)-1-piperazinyl]alkyl]-8-azaspiro[4.5]decane-7,9-dione s represented by the structural formula ##STR1## wherein A represents an alkylene group having from 2 to 6 carbon atoms, have pharmacological utility as tranquilizing and anti-emetic agents.
Methods are also known for preparing the compounds of Formula I by using, as starting materials, 1-(cyanoalkyl)-4-(2-pyrimidyl)piperazines represented by the structural formula ##STR2## wherein R represents an alkylene group having from 1 to 5 carbon atoms. Such methods are described, for example, in U.S. Pat. Nos. 3,976,776; 3,907,801; 3,717,634; and 3,398,151, and the disclosures of these patents are hereby incorporated herein by reference.
The aforesaid patents, taken with Howard et al, J. Org. Chem., Vol. 18, pp. 1484-1488 (1953) (which is referred to therein) also describe a method for preparing the compounds of Formula II. For example, for preparing 1-(3-cyanopropyl)-4-(2-pyrimidyl)piperazine, that method includes reacting piperazine with 2-chloropyrimidine to obtain 1-(2-pyrimidyl)piperazine, which is then reacted with 3-chlorobutyronitrile to obtain the desired compound.
However, such a method has a number of drawbacks. Namely, the yields are relatively poor, and the starting material, 2-chloropyrimidine, is relatively expensive. The known method, as described in the references noted above, for producing the Formula II compounds entails a considerable waste of the expensive 2-chloropyrimidine. Part of the reason for the waste is that in reacting piperazine with 2-chloropyrimidine to obtain 1-(2-pyrimidyl)piperazine, a very significant amount of by-product comprising 1,4-bis(2-pyrimidyl)piperazine also results and must be separated out, thus wasting large amounts of 2-chloropyrimidine.
Accordingly, a need exists for alternative syntheses of the Formula II compounds which are more economical than the syntheses described in the prior art. The present invention provides such an alternative. It involves preparation of a novel 2-pyrimidyl alkanesulfonate which is then reacted with a novel cyanoalkylpiperazine.
In regard to preparation of alkanesulfonates, Crossland et al, J. Org. Chem., Vol. 35, pp. 3195-3196 (1970) describes a method of preparing hydrocarbon methanesulfonates by reacting methanesulfonyl chloride with a hydroxyhydrocarbon in an inert solvent in the presence of a base, but it does not describe such a method for preparation of a heterocyclic alkanesulfonate from a hydroxyheterocycle, such as 2-hydroxypyrimidine.
It should be noted that we also have invented other alternative syntheses of Formula II compounds and have invented other novel compounds which are useful in these syntheses. These other invention are described in our co-pending U.S. patent applications, Ser. No. 407,216, filed Aug. 11, 1982, entitled "Cyanoalkylpiperazines and Methods for Their Preparation and Use" (now U.S. Pat. No. 4,515,947, issued May 7, 1985) and Ser. No. 407,215, filed Aug. 11, 1982, entitled "Acid Salts of 1-(Cyanoalkyl)-4-guanylpiperazines and Methods for Their Preparation and Use," the disclosures of which are hereby incorporated herein by reference.